Synthesis and Identification of Pregnenolone Derivatives as Inhibitors of Isozymes of 5a-Reductase


Por: Chávez-Riveros A., Bratoeff E., Heuze Y., Soriano J., Moreno I., Sánchez-Márquez A., Cabeza M.

Publicada: 1 nov 2015
Resumen:
Hyperplasia of the prostate gland and prostate cancer have been associated with high levels of serum 5a-dihydrotestosterone. This steroid is formed from testosterone by the activity of the enzyme 5a-reductase (5a-R) present in the prostate. Thus, inhibition of this enzyme could be a goal for therapies to treat these diseases. This study reports the synthesis and effects of five different 21-esters of pregnenolone derivatives as inhibitors of 5a-R types 1 and 2. The activity of these steroidal compounds was determined using in vivo and in vitro experiments. The results indicate that of the five steroids studied, the 21(p-fluoro)benzoyloxypregna-4,16-diene-3,6,20-trione derivative, whose structure has not yet been reported, has the best molecular conformation to inhibit the in vitro activity of both types of 5a-R. In addition, this steroid also displayed activity in vivo. Apparently, its pharmacological effect was increased by the presence of a keto group at C-6, because this group decreased the possibility that the steroid would be metabolized by hepatic enzymes. In addition, the double bond present at C-4 of this compound also enhanced its inhibitory activity on 5a-R, and the C-21 ester moiety increased its liphophilicity. Therefore, its solubility in the cell membrane and its pharmacological activity were both increased. © 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Filiaciones:
Chávez-Riveros A.:
 Univ Nacl Autonoma Mexico, Fac Quim, Dept Farm, Mexico City 04510, DF, Mexico

Bratoeff E.:
 Univ Nacl Autonoma Mexico, Fac Quim, Dept Farm, Mexico City 04510, DF, Mexico

Heuze Y.:
 Departamento de Sistemas Biolõgicos y de Producciõn Agrícola y Animal, Universidad Autõnoma Metropolitana-Xochimilco, Ciudad de México, México, D. F., Mexico

Soriano J.:
 Departamento de Patología, Hospital General de México, México, D. F., Mexico

Moreno I.:
 Departamento de Sistemas Biolõgicos y de Producciõn Agrícola y Animal, Universidad Autõnoma Metropolitana-Xochimilco, Ciudad de México, México, D. F., Mexico

Sánchez-Márquez A.:
 Departamento de Sistemas Biolõgicos y de Producciõn Agrícola y Animal, Universidad Autõnoma Metropolitana-Xochimilco, Ciudad de México, México, D. F., Mexico

Cabeza M.:
 Departamento de Sistemas Biolõgicos y de Producciõn Agrícola y Animal, Universidad Autõnoma Metropolitana-Xochimilco, Ciudad de México, México, D. F., Mexico
ISSN: 03656233
Editorial
WILEY-V C H VERLAG GMBH, BOSCHSTRASSE 12, D-69469 WEINHEIM, GERMANY, Alemania
Tipo de documento: Article
Volumen: 348 Número: 11
Páginas: 808-816
WOS Id: 000364342100005
ID de PubMed: 26377677